DESCRIPTION (Applicant's Description) Ovarian cancer remains the most lethal gynecologic malignancy, as patients commonly fail surgical debulking and multiple regimens of conventional chemotherapy. Decades of research in dose escalation, drug development and novel delivery systems has failed to show any significant advance in survival. Understanding of the molecular basis of ovarian cancer, in particular the role of the tumor suppressor gene p53, has stimulated ideas on new therapeutic gene targeting strategies. In vitro and in vitro preclinical data support the use of adenoviral p53 gene therapy (Ad5-p53) for use in the treatment of human solid tumors. Since the spread of advanced ovarian cancer typically remains in the peritoneal compartment and tumor cells in ascites are easily accessible for biologic studies, intraperitoneal administration of Ad5-p53 is an ideal model to use in translating recent laboratory developments into clinical trials. This proposed phase I clinical trial will evaluate the hypothesis that intraperitoneal administration of adenoviral p53 gene therapy in patients with ovarian cancer will result in a minimally toxic growth inhibition and tumor reduction by transient induction of tumor cell apoptosis. We will accomplish this by the following primary specific aims: Specific Aim 1: To determine the maximal tolerated dose and toxicities of intraperitoneally administered adenoviral-based p53 gene therapy in patients wit ascites from advanced, recurrent or persistent ovarian carcinoma failing conventional chemotherapy. Dose escalations of intraperitoneal administration of Ad5-p53 will be studied in patients accrued in a standard clinical phase I trial. Organ toxicities, side effect profiles as well as the maximal tolerated dose (MTD) will be determined. Specific Aim 2: To evaluate the Ad5-p53 vector pharmacokinetics and biologic efficacy including gene transduction, transgene expression, and mechanism bf tumor cell kill. Tumor cells in ascites will be used to study the effect and time course of action of AdS-p53. Methods such as immunohistochemistry, PCR, RT-PCR with vector specific primers, flow cytometry and TUNEL assays will be used. Specific Aim 3: To determine the human systemic and intraperitoneal immunologic response to the viral vector, systemic biodistribution, potential for vector infectivity and vector inactivation, following intraperitoneal administration of ad5-p53. Host response to Ad5-p53 will be studied on serum and ascitic supernatant by cytopathic effect (CPE) assays, complement and CH50 measurement and host antibody measurements. This will determine the safety and unlikely infectivity profile. Specific Aim 4: To determine the response rate to the Ad-p53 vector in patients with advanced, recurrent or persistent ovarian cancer. A secondary endpoint of response will be measured by clinical or radiographic tumor measurements, indirect measurements of ascites production and changes in symptom profile.